CD4, a surface glycoprotein receptor found on a subset of T lymphocytes known as CD4+ cells, is involved in Class II major histocompatibility complex (MHC) recognition and appears to be the physiological receptor for Class II MHC. Human CD4 is also the receptor for the gp120 envelope glycoprotein of the human immunodeficiency virus (HIV) and is essential for virus entry into the host cell, and for membrane fusion, both of which contribute to cell-to-cell transmission of the virus and to its cytopathic effects. It is known that HIV causes AIDS by attacking the immune system and destroying CD4+ cells, thus leaving the body defenseless against attack by microbial and other viral pathogens. CD4 has been shown to be the major route of entry of HIV into CD4+ cells by binding to CD4.
Considerable effort has been expended in studying the CD4gp120 interaction and in trying to interfere with or inhibit that interaction, in an attempt to provide a means by which the life threatening effects of HIV infection can be slowed or reversed. Thus far, a small number of anti-viral drugs have been developed to interfere with infection of cells by HIV and its subsequent effects, such as zidovudine (also known as AZT) or dideoxyinosine (ddI). A means by which to prevent HIV infection of CD4-bearing lymphocytes, which make up approximately 60-80% of the total circulating T lymphocyte population, would be of great value, particularly in light of the fact that HIV infection of such cells can cause total collapse of the immune system and would be expected to avoid development of a viral resistance to the therapy. One compound, dextran-sulfate, was thought to interfere with CD4gp120 interaction. However, the compound resulted in unacceptable levels of anti-coagulation activity. Recently, dextran sulfate reportedly failed to suppress infection by monocytotropic HIV-1 isolates (Meylan, P. R. A. et al., Antimicrob. Agents Chemother. 38:2910-2916 (1994)). It would be of further value to develop agents that can be used to treat CD4-related diseases such as AIDS-related complex (ARC), AIDS-related dementia and non-symptomatic HIV infection which avoid significant levels of anti-coagulation activity.
Many condensation polymers of formaldehyde and aromatic sulfonic acids have been previously described. U.S. Pat. No. 4,604,404 discloses the use of some such polymers as antiviral agents against the Herpes simplex virus. However, the reference does not teach or suggest the use of such compounds in the treatment of HIV infections and related diseases and conditions.
This invention relates to the discovery that condensation polymers of aromatic sulfonic acids and an aldehyde and fractions thereof, particularly naphthalenesulfonic acid formaldehyde polymers (such as PRO 1041, PRO 1135 and PIC 024.4, and fractions thereof defined below) can abrogate HIV gp120 binding to CD4, as demonstrated in CD4/gp120 binding assays. Compounds of the present invention have been shown to have little to no cytotoxicity and inhibitory activity to antigen induced T-lymphocyte proliferation and exhibit specificity as manifested by lack of inhibition in CD2/LFA-3 (lymphocyte function-associated antigen) (CD58) binding assay. Based on these findings, condensation polymers of aromatic sulfonic acids and an aldehyde and fractions thereof can be used as therapeutic agents for the prophylaxis or treatment of HIV infection, acquired immunodeficiency syndrome (AIDS), as well as AIDS-related complex (ARC), AIDS-related dementia and non-symptomatic HIV infection. The compounds can also be used to treat a blood preparation in vitro to prevent HIV infection of CD4+ cells present in the blood preparation.